Synthesis of Highly Substituted Adamantanones from Bicyclo[3.3.1

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Synthesis of Highly Substituted Adamantanones from Bicyclo[3.3.1]nonanes Michael E Jung, and Gloria S Lee J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501368d • Publication Date (Web): 02 Oct 2014 Downloaded from http://pubs.acs.org on October 3, 2014

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The Journal of Organic Chemistry

Synthesis of Highly Substituted Adamantanones from Bicyclo[3.3.1]nonanes Michael E. Jung* and Gloria S. Lee Department of Chemistry and Biochemistry, University of California, Los Angeles, California 900951569 [email protected] RECEIVED DATE (to be automatically inserted)

Abstract Trifluoromethanesulfonic acid and other electrophiles promote formation of the adamantanone core from the readily accessible 1,5-dimethyl-3,7-dimethylenebicyclo[3.3.1]nonan-9-one 2. Since the adamantyl cation 3 can be trapped by a range of nucleophiles, including aromatic and heteroaromatic rings, alcohol, nitriles, and halides, access to a wide variety of functionality at the newly formed tertiary position is provided.

The diamond-like structure of adamantane has fascinated chemists since its discovery in petroleum in 1933.1 Studies have shown that adamantane is the most stable of the C10H16 isomers and can be easily prepared by the Lewis acid promoted rearrangement of other C10H16 species, e.g., tetrahydrodicyclopentadiene.2 The first instance of the adamantane structure in drugs involved 1-aminoadamantane, amantadine, a selective antiviral agent, which was used against influenza upon its approval in 1966.3 Since then, a number of 1-aminoadamantanes have been synthesized and one, 3,5-dimethyl-1-aminoadamantane, memantine, has been approved for the treatment of Alzheimer’s disease.4 However, the biological mechanism of action of the adamantane derivatives is still unclear. 1

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Figure 1. Rugulosone, amantadine, and memantine structures.

For a project aimed at the total synthesis of rugulosone, 1,5 (Figure 1) we prepared 1,5-dimethyl3,7-dimethylenebicyclo[3.3.1]nonan-9-one 2 by the very efficient quadruple alkylation of 3-pentanone with 1,1-bis(chloromethyl)ethylene, a reaction that proceeded in 90% yield.6 We were interested in seeing if this bis(methylene) system could be used to efficiently construct various substituted adamantanones, which might serve as precursors to the corresponding adamantanes. The ability to construct a large variety of substituted adamantanones in a highly efficient and simple manner could allow for more rapid testing of derivatives to study both the biological activity and the mechanism of action of this class of compounds. The Friedel-Crafts alkylation of benzenoid aromatic rings with the adamantane core has been reported occasionally but harsh conditions, including high temperature, long reaction times, and high pressure mercury lamps, were often employed.7 In many cases, a multistep procedure is involved in which a 1-haloadamantane is first formed and then used to generate a carbocation at the tertiary position, which is subsequently trapped by a nucleophile. Although there is one example of the cyclization of the simple unsubstituted 3,7-dimethylenebicyclo[3.3.1]nonane in anisole as solvent giving the aryl adamantine,8 to our knowledge, no systematic study of the Friedel-Crafts alkylation of adamantyl cations generated by this type of cyclization has been carried out. This limited reaction scope therefore prompted us to investigate a more efficient way of rapidly constructing substituted adamantanones. 2


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Synthesis of Adamantanones from 2. We now present a new and efficient method for the construction of adamantan-2-ones substituted at the 7-position with aryl, heteroaryl, alkoxy, amido, and alkynyl groups, starting from the 1,5-dimethyl-3,7-dimethylenebicyclo[3.3.1]nonan-9-one core 2. We envisioned forming the adamantyl cation with acid, followed by trapping with a nucleophile to obtain the tetrasubstituted adamantanone core. Consequently, we screened various acidic conditions for the formation of the desired product, 1,3,5-trimethyl-7-phenyladamantan-2-one 4a, from 2 (Table 1). Table 1. Conversion of diene 2 to trimethylphenyladamantanone 4aa

Entry 1 2 3 4 5 6 7 8

Acid TMSOTf BF3·OEt2 AlCl3 H2SO4 TFA TfOH Cu(OTf)2 None

Yield (%) 65 78 47 21 59 90 0 0

a

Reaction conditions: 2 (1.05 mmol), acid (1.2 equiv), benzene (5 mL), Ar, 3 h.

Without the presence of an added nucleophile, the cation can be quenched by the benzene solvent. Thus, treatment of the diene 2 with trimethylsilyl triflate in benzene afforded the 7-phenyl-substituted adamantanone 4a in 65% yield. Other protic and Lewis acids produced the same product 4a in moderate to good yields, with trifluoromethanesulfonic acid, triflic acid, being the best of those tested, giving the desired product in 90% yield. Some Lewis acid catalysts, e.g., cupric triflate, did not provide any product but only returned starting material. Substrate Scope. Next, we investigated the substrate scope of our reaction using the same mild conditions and short reaction times (Table 2). Various aromatic rings with electron-donating groups 5a-e reacted as good nucleophiles to produce the substituted adamantanones 4a-e in moderate yields. Thus toluene 5b gave a 76% combined yield of a 3:1 mixture of the 4-methyl and 2-methyl products 4b and 4b’. p-Xylene 5c gave the expected product 4c in 47% isolated yield; similarly, m-dimethoxybenzene 5d 3 ACS Paragon Plus Environment


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afforded the expected product 4d in 47% yield. The more hindered 1,3,5-trimethoxybenzene 5e gave the expected product 4e in only 36% yield, perhaps due to the steric hindrance of the only available aromatic position. Again, there have been scattered reports of the trapping of adamantyl cations with benzenoid Table 2. Reaction of 2 with aromatic rings 5 to give 4.a

Entry 1b 2b

Nu 5a 5b

3b 4 5

5c 5d 5e

R2 H H Me Me OMe OMe

R3 H H H H H H

R4 H Me H H OMe OMe

R5 H H H Me H H

R6 H H H H H OMe

Yield (%) 4a, 90 4b, 57 4b’, 19 4c, 47 4d, 47 4e, 36

a

Reaction conditions: 2 (1.05 mmol), TfOH (1.2 equiv), nucleophile (5.0 equiv.), CH2Cl2 (5 mL), Ar, 3 h, unless otherwise specified. bReactions are performed with nucleophile as solvent.

nucleophiles but no systematic study has been reported.9 As far as we can tell, no heterocycles have ever been used to trap an adamantyl cation under these conditions. Therefore we studied the use of several 5membered heterocyclics in this regard (Table 3). Furan and N-methylindole gave very poor results with a multitude of unidentified products being formed. But the reaction of 2 in the presence of triflic acid with N-methylpyrrole 5f gave a mixture of the 2- and 3-substituted pyrrole products, 4f and 4f’, in yields of 33% and 17% respectively. The assignment of the structures was based on the pattern of the absorptions in the proton NMR spectrum and matched literature data.10 In this case, the ratio of the trapping at C2 vs C3 (1.9:1) is somewhat surprising, given that the reported ratio of trapping of a tert-butyl cation with Nmethylpyrrole is 1:1.4 (C2:C3).11 Likewise, reaction of 2 with thiophene 5g in the presence of triflic acid afforded the 2- and 3-substituted products, 4g and 4g’, in a 1.2:1 ratio in yields of 26% and 21%. The assignment was made by comparing the coupling constants for the three aromatic protons and by analogy to literature data.12 In addition to trapping the adamantyl cation, generated from 2 by protonation with triflic acid, with aromatic nucleophiles, we also investigated trapping with other simple nucleophiles. Again there 4


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Table 3. Reactions of 2 with nucleophiles to give 4.

Entry 1

Nuc

R

Yield (%) 4f, 33

4f’, 17

2

4g, 26 4g’, 21

3b 4b 5c 6 7 8

HOMe HOAc H2 O HOCH2CCH HOPh HOTf

OPh OSO2CF3

9b 10

CH3CN

NHCOMe

OMe OAc OH

4h, 52 4i, 88 4j, 74 4k, 35 4l, 36 4m, trace 4n, trace

4o, 88 4p, 44

a

Reaction conditions: 2 (1.05 mmol), TfOH (1.2 equiv), nucleophile (5.0 equiv.), CH2Cl2 (5 mL), unless otherwise specified. Reactions performed with nucleophile as solvent. cconc. H2SO4 as solvent.

b

are reports of such nucleophilic trapping in the literature13 but no systematic study has been carried out. Thus we treated the diene 2 with triflic acid in the presence of various nucleophiles with the results shown in Table 3. Methanol and acetic acid as nucleophilic solvents gave good yields of the expected trapping of the oxygen atom to produce 4h and 4i in 52% and 88% yield respectively. The tertiary alcohol 4j could also be prepared by treating 2 with conc. sulfuric acid in 74% yield. Propargyl alcohol also trapped on oxygen to give the propargyl ether 4k in 35% yield. Somewhat surprisingly, phenol gave only trapping on the oxygen atom to give 4l in 36% yield with no evidence for trapping on carbon, 5



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either C4 or C2, being observed. In the absence of any external trapping agent, one obtains trace amounts of the triflate 4m and the symmetrical ether 4n. One can also carry out a Ritter reaction, namely treatment of 2 with triflic acid in acetonitrile as solvent to generate the acetamide 4o in 88% yield.14 This trapping would be useful for preparing analogues of memantine. Finally we could also effect C-C bond formation of a non-aromatic substrate, namely trimethylsilyl acetylene to give the acetylene product 4p in 44% yield. We also examined the addition of electrophiles other than proton to one of the exocyclic methylenes of 2 with the idea of triggering the cyclization to produce the adamantyl cation, which could then be trapped with simple nucleophiles. Reports of such dual addition of electrophiles and nucleophiles to similar dienes have appeared in the literature,15 but here again no systematic study has been carried out. Thus treatment of the diene 2 with N-bromosuccinimide (NBS) in aqueous DMSO or in methanol gave the bromomethyl alcohol and methyl ether, 4q and 4r, in 66% and 89% yields, respectively. Addition of either bromine or iodine to 2 in dichloromethane gave the dihalo products, 4s and 4t, in yields of 88% and 77% respectively.16 Non-halogenated electrophiles could also be used. Table 4. Reactions of 2 with both electrophiles and nucleophiles to give 4.

Entry 1 2 3 4 5

Conditions NBS, aq. DMSO NBS, MeOH Br2, CH2Cl2 I2, CH2Cl2 Hg(OAc)2, MeOH; aq. NaCl

R1 Br Br Br I HgCl

R2 OH OMe Br I OMe

Yield (%) 4q, 66 4r, 89 4s, 88 4t, 77 4u, 26

Thus addition of mercuric acetate to 2 in methanol provided the acetoxymercurio ether, which, for ease of isolation, was converted into the chloromercurio ether by addition of NaCl to give 4u in 26% yield. We tested the generality of this process by examining the cyclization of other substrates, namely the three analogues of the dimethyl compound 2 with ethyl, propyl, and phenyl groups a to the ketone. The additional di-(exo)methylene compounds, 6a-c, were prepared from the corresponding substituted ketones and the bis(chloromethyl)ethylene.6 Treatment of all of these three analogues 6a-c with triflic 6


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acid in benzene afforded the expected adamantanone products 7a-c in good yields (Scheme 1). No attempts at optimization of these yields have been made. Thus simple alkyl and aryl substituents are well tolerated. Scheme 1. Cyclization of analogues 6 to give adamantanones 7.

The mechanism of this process (Scheme 2) would involve the addition of an electrophile, E+ (H+, X+) to one of the two identical alkenes of 2 from the exo face to generate the tertiary carbocation A. Cyclization of the other alkene on to this carbocation would then generate the adamantyl cation B, despite the instability inherent in a non-planar cation. Attack of the nucleophile on B, with loss of a proton, would afford the observed products 4. Though the formation of adamantyl cations is well known,17 they are often formed from adamantyl halides and not from bicyclo[3.3.1]diene systems. Scheme 2. Mechanism of 2 forming adamantane core 4.

We have shown that the acetamide 4o, obtained from 2 by the Ritter reaction, can be hydrolyzed to the amine 8, an analogue of memantine, in 97% yield under strongly acidic conditions (Scheme 3), Scheme 3. Hydrolysis of 4o giving memantine analog 8.

7



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conc. HCl in ethanol in a sealed tube at 100 °C for 3 days.

Conclusion In summary, we have shown that the readily available 1,5-dimethyl-3,7-dimethylenebicyclo[3.3.1]nonan-9-one 2 can be easily converted into a wide variety of adamantanone derivatives by treatment with various electrophiles, especially proton, in the presence of a nucleophilic trapping agent. Other analogues, e.g., 6abc, also give the corresponding adamantanones 7abc.

8


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Experimental Section General: All reactions were carried out under an argon atmosphere unless otherwise specified. Dichloromethane was distilled from calcium hydride under an argon atmosphere. Trifluoromethanesulfonic acid of 99% purity was used. All other solvents or reagents were purified according to literature procedures. 1H NMR spectra were recorded on a high field NMR spectrometer (at 500 MHz) and are reported relative to deuterated solvent signals. Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm), multiplicity, coupling constant (Hz) and integration. Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and b, broad. 13C NMR spectra were recorded on a high field NMR spectrometer (at 125 MHz). Data for 13C NMR spectra are reported in terms of chemical shift and are reported in parts per million (ppm, δ). Thin-layer chromatography (TLC) was carried out using pre-coated silica gel sheets (Merck 60 F254). Visual detection was performed using phosphomolybdic acid or iodine. Flash chromatography was performed using SilicaFlash™ P60 (60 A, 40-63 µm) silica gel with compressed air. High resolution mass spectrometry was taken on a quadrupole mass spectrometer equipped with a DART ion source. General Procedure for Acid Promoted Cyclization in Benzene To a solution of diene 2 (0.200 g, 1.05 mmol) in benzene (5 mL) was added trifluoromethanesulfonic acid (0.111 mL, 1.26 mmol) at 0 ˚C. The reaction was let warm to 21 ˚C and stirred for 3 h. The solution was quenched with a saturated solution of NaHCO3 (10 mL). The mixture was extracted with hexanes (3 X 20 mL) and the combined organic extracts were dried with MgSO4, filtered and concentrated in vacuo to give a crude yellow oil. Purification by flash column chromatography on silica gel (19:1 hexanes/ethyl acetate) afforded the trimethylphenyladamantanone 4a (0.253 g, 0.94 mmol, 90%) as a light yellow oil.

General Procedure for the Triflic Acid Promoted Cyclization and Trapping of Nucleophiles To a solution of diene 2 (0.200 g, 1.05 mmol) in dichloromethane (5 mL) was added mdimethoxybenzene 5d (0.030 mL, 5.25 mmol) then trifluoromethanesulfonic acid (0.111 mL, 1.26 9



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mmol) at 0 ˚C. The reaction was let warm to 21 ˚C stirred for 3 h. The solution was quenched with a saturated solution of NaHCO3 (10 mL). The mixture was extracted with dichloromethane (3 X 20 mL) and the combined organic extracts were dried with MgSO4, filtered and concentrated in vacuo to give a crude light yellow oil. Purification by flash column chromatography on silica gel (19:1 hexanes/ethyl acetate) afforded the 2,4-dimethoxyphenyladamantanone 4d (0.162 g, 0.49 mmol, 47%) as a light yellow oil.

General Procedure for the Addition of Various Electrophiles and Subsequent Trapping of Nucleophiles To a solution of diene 2 (0.100 g, 0.525 mmol) in 1:1 methanol:dichloromethane (6 mL) was added NBS (0.121 g, 0.068 mmol) at 0 ˚C. The reaction was warmed to 21 ˚C and stirred for 3 h. The solution was quenched with a saturated solution of NaHCO3 (10 mL). The mixture was extracted with dichloromethane (3 X 15 mL) and the combined organic extracts were dried with MgSO4, filtered and concentrated in vacuo to give crude bromomethyl methoxyadamantanone 4r (0.140 g, 89%) as a light yellow oil.

1,5-Dimethyl-3,7-dimethylenebicyclo[3.3.1]nonan-2-one, 2. To a suspension of 60% NaH in mineral oil (0.176 g, 4.40 mmol) (washed three times with hexanes) in toluene (5 mL) was added 3-pentanone (0.086 g, 1.00 mmol) in toluene (2 mL) dropwise. A solution of 1-chloro-2-(chloromethyl)-2-propene (0.254 g, 2.20 mmol) in toluene (2mL) was added dropwise and the reaction was refluxed overnight. The solution was then cooled to room temperature and quenched with a saturated solution of NH4Cl (20 mL). The mixture was extracted with ethyl acetate (3 X 20 mL), washed with brine (20 mL) and the combined organic extracts were dried with MgSO4, filtered and concentrated in vacuo to give a crude yellow oil. Purification by flash column chromatography on silica

10


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gel (19:1 hexanes/ethyl acetate) afforded the bicyclononanone 2 (0.171 g, 0.90 mmol, 90%) as a light yellow oil.

5-Hydroxy-1,3,7-trimethyladamantan-2-one, 4j. To a solution of the diene 2 (0.050 g, 0.26 mmol) in DMSO (1 mL) was added conc. H2SO4 (1 mL) and water (0.1 mL) at 0 ˚C. The reaction was let warm to room temperature and stirred for 3 h. The solution was quenched with a saturated solution of NaHCO3 (10 mL), extracted with dichloromethane (3 X 20 mL) and the combined organic extracts were washed with water (10 mL) and brine (10mL), dried with MgSO4, filtered and concentrated in vacuo to give hydroxyadamantanone 4j (0.041 g, 0.20 mmol, 74%) as a light yellow oil.

5-Amino-1,3,7-trimethyladamantan-2-one, 8. To a solution of the acetamide 4o (0.087 g, 0.35 mmol) and ethanol (2 mL) was added conc. HCl (0.5 mL) and water (0.1 mL) in a sealed tube. The vessel was heated to 100 ˚C for 3 d. The solution was then cooled to 0 ˚C and quenched with a saturated solution of NaHCO3 (20 mL). The mixture was extracted with dichloromethane (3 X 20 mL), washed with brine (20 mL) and the combined organic extracts were dried with MgSO4, filtered and concentrated in vacuo to give the crude 5-aminoadamantanone 8 (0.070 g, 0.34 mmol, 97%) as a yellow oil.

1,3,5-Trimethyl-7-phenyladamantan-2-one, 4a. 1H NMR (500 MHz, CDCl3) δ 7.38 – 7.31 (m, 4H), 7.23 (bt, J = 7.0 Hz, 1H), 1.98 (bd, J = 12 Hz, 2H), 1.88-1.85 (m, 4H), 1.64 (bd, J = 12.5 Hz, 2H), 1.571.54 (m, 4H), 1.01 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 218.5, 147.7, 128.3, 126.2, 124.9, 52.5, 51.5, 48.1, 45.9, 38.4, 32.1, 28.8, 22.6. HRMS (ESI, m/z): 269.1895, calculated for C19H24OH (M+H)+ 269.1905.

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1,3,5-Trimethyl-7-(4-methylphenyl)adamantan-2-one,

4b,

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and

1,3,5-Trimethyl-7-(2-

methylphenyl)adamantan-2-one, 4b’. 1H NMR (500 MHz, CDCl3) δ 7.25 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 2.33 (s, 3H), 1.96 (m, 2H), 1.85 (m, 4H), 1.65 (bd, J = 12.5 Hz, 2H), 1.54 (m, 2H), 1.00 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 218.6, 144.7, 135.7, 129.1, 124.8, 52.5, 51.5, 48.1, 45.9, 38.5, 32.1, 28.8, 22.8, 20.9. HRMS (ESI, m/z): 283.2051, calculated for C20H26OH (M+H)+ 283.2062.

5-(2,5-Dimethylphenyl)-1,3,7-trimethyladamantan-2-one, 4c. 1H NMR (500 MHz, CDCl3) δ 7.13 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 2.55 (s, 3H), 2.32 (s, 3H), 2.07 (m, 4H), 1.99 (s, 2H), 1.64 (d, J = 12.0 Hz, 2H), 1.56 (d, J = 12.0 Hz, 2H), 1.03 (s, 6H), 1.02 (s, 3H).

13

C NMR (125

MHz, CDCl3) δ 218.6, 144.1, 135.4, 133.4, 132.7, 127.0, 126.9, 52.4, 49.8, 46.2, 45.9, 39.9, 32.2, 29.0, 23.2, 22.8, 21.2. HRMS (ESI, m/z): 297.2197, calculated for C21H28OH (M+H)+ 297.2218.

1,3,5-Trimethyl-7-(2,4-dimethoxyphenyl)adamantan-2-one, 4d. 1H NMR (500 MHz, CDCl3) δ 6.46 (s, 1H), 6.44 (m, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 2.15 (d, J = 11.5 Hz, 2H), 1.97 (d, J = 9 Hz, 2H), 1.55 (m, 6H), 0.98 (s, 9H).

13

C NMR (125 MHz, CDCl3) δ 219.4, 159.4, 159.2, 127.5, 126.9, 103.6, 99.7,

55.2, 54.9, 52.7, 49.2, 45.9, 45.8, 38.4, 32.0, 29.0, 22.8. HRMS (ESI, m/z): 329.2100, calculated for C21H28O3H (M+H)+ 329.2117.

1,3,5-Trimethyl-7-(2,4,6-trimethoxyphenyl)adamantan-2-one, 4e. 1H NMR (500 MHz, CDCl3) δ 6.13 (s, 2H), 3.78 (s, 3H), 3.74 (s, 6H), 2.36 (bd, J = 12.5 Hz, 2H), 2.25 (bd, J = 12 Hz, 2H), 2.16 (s, 2H), 1.53 (s, 4H), 0.95 (s, 6H), 0.92 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 219.9, 160.5, 158.9, 115.4, 93.1, 55.8, 55.1, 52.5, 50.4, 46.1, 45.8, 41.1, 31.9, 29.3, 23.0. HRMS (ESI, m/z): 359.2210, calculated for C22H30O4H (M+H)+ 359.2222.

12


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1,3,5-Trimethyl-7-(1-methyl-1H-pyrrol-2-yl)adamantan-2-one, 4f. 1,3,5-Trimethyl-7-(1-methyl1H-pyrrol-3-yl)adamantan-2-one, 4f’. 1H NMR (500 MHz, CDCl3) δ 6.53 (t, J = 2.5 Hz, 1H), 6.48 (t, J = 2.5 Hz, 1.9H) 6.40 (t, J = 2.0 Hz, 1H), 6.04 (t, J = 2.0 Hz, 1H), 6.01 (t, J = 2.5 Hz, 1.9H), 5.94 (t, J = 2 Hz, 1.9H), 3.76 (s, 5.7H), 3.60 (s, 3H), 2.05 (d, J = 12.0 Hz, 4H), 1.95 – 1.87 (m, 10H), 1.77 (m, 4H), 1.62 (d, J = 12.5 Hz, 4H), 1.60 – 1.50 (m, 8H), 0.99 (s, 18H), 0.96 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 219.1, 218.2, 138.0, 132.6, 124.4, 121.6, 116.8, 106.1, 105.9, 105.1, 52.7, 52.4, 49.8, 49.1, 46.5, 45.9, 45.6, 37.2, 36.4, 36.1, 34.6, 32.0, 31.8, 28.8, 28.7, 22.65, 22.60. HRMS (ESI, m/z): 272.2005, calculated for C18H25NOH (M+H)+ 272.2014.

1,3,5-Trimethyl-7-(thiophen-2-yl)adamantan-2-one, 4g. 1,3,5-Trimethyl-7-(thiophen-3-yl)adamantan-2-one, 4g’. 1H NMR (500 MHz, CDCl3) δ 7.28 (dd, J = 5.0, 3.0 Hz, 1H), 7.16 (dd, J = 5.0, 1.0 Hz, 1H), 7.07 (dd, J = 5.0, 1.5 Hz, 1H), 6.98 (dd, J = 3.0, 1.5 Hz, 1H), 6.94 (m, 1H), 6.84 (dd, J = 3.5, 1.5 Hz, 1H), 2.02 (d, J = 12.0 Hz, 2H), 1.97 (d, J = 12.0 Hz, 2H), 1.90 (m, 4H), 1.83 (m, 4H), 1.62 (d, J = 12 Hz, 4H), 1.56 (m, 4H), 1.00 (s, 18H).

13

C NMR (125 MHz, CDCl3) δ 218.3, 217.8, 153.8, 149.8,

126.5, 125.6, 125.3, 122.6, 121.2, 118.2, 52.7, 52.5, 52.4, 51.6, 49.7, 48.4, 46.0, 45.9, 38.1, 37.3, 32.3, 32.0, 28.7, 28.5, 22.5, 22.4. HRMS (ESI, m/z): 275.1460, calculated for C17H22OSH (M+H)+ 275.1470.

5-Methoxy-1,3,7-trimethyladamantan-2-one, 4h. 1H NMR (500 MHz, CDCl3) δ 3.25 (s, 3H), 1.77 (bd, J = 15 Hz, 2H), 1.68-1.65 (m, 4H), 1.53 (bd, J = 15 Hz, 2H), 1.47-1.43 (m, 2H) 0.98 (s, 3H), 0.97 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 217.3, 72.5, 52.5, 48.8, 47.7, 46.1, 45.4, 33.5, 28.2, 22.2. HRMS (ESI, m/z): 223.1689, calculated for C14H22O2H (M+H)+ 223.1698.

3,5,7-Trimethyl-4-oxoadamantan-1-yl acetate, 4i. 1H NMR (500 MHz, CDCl3) δ 2.13 – 2.02 (m, 6H), 1.97 (s, 3H), 1.52 (s, 4H), 0.96 (bs, 9H). 13C NMR (125 MHz, CDCl3) δ 216 4, 170.1, 79.2, 52.1, 47.7,

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46.3, 45.2, 33.8, 28.0, 22.0, 21.9. HRMS (ESI, m/z): 251.1638, calculated for C15H22O3H (M+H)+ 251.1647.

5-Hydroxy-1,3,7-trimethyladamantan-2-one, 4j. 1H NMR (500 MHz, CDCl3) δ 1.77 (m, 2H), 1.65 (m, 4H), 1.49 (m, 4H), 1.23 (s, 1H), 0.97 (s, 3H), 0.95 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 217.4, 69.0, 52.3, 51.8, 49.8, 46.4, 33.9, 28.1, 22.1. HRMS (ESI, m/z): 209.1538, calculated for C13H20O2H (M+H)+ 209.1542.

1,3,5-Trimethyl-7-(prop-2-yn-1-yloxy)adamantan-2-one, 4k. 1H NMR (500 MHz, CDCl3) δ 4.14 (d, J = 2.5 Hz, 2H), 2.39 (t, J = 2 Hz, 1H), 1.83 (bd, J = 11 Hz, 2H), 1.73 (s, 2H), 1.75-1.72 (m, 2H), 1.52 (bd, J = 12.5 Hz, 2H), 1.46 (bd, J = 10 Hz, 2H) 0.98 (s, 3H), 0.97 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 217.0, 81.2, 74.4, 73.6, 52.2, 49.8, 48.1, 46.3, 45.9, 33.7, 28.2, 22.2. HRMS (ESI, m/z): 247.1686, calculated for C16H22O2H (M+H)+ 247.1698.

1,3,5-Trimethyl-7-phenoxyadamantan-2-one, 4l. 1H NMR (500 MHz, CDCl3) δ 7.28 (bt, J = 8.5 Hz, 2H), 7.13 (bt, J = 7.5 Hz, 1H), 6.98 (bd, J = 8.5 Hz, 2H), 1.91 (bd, J = 10.5 Hz, 2H), 1.81 (s, 2H), 1.791.78 (m, 2H), 1.52 (bd, J = 12.5 Hz, 2H), 1.47-1.44 (m, 2H), 0.98 (s, 3H), 0.97 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 217.0, 153.8, 129.0, 124.7, 124.2, 77.5, 52.3, 49.3, 47.2, 46.4, 33.9, 28.2, 22.2. HRMS (ESI, m/z): 285.1849, calculated for C19H24O2H (M+H)+ 285.1855.

3,5,7-Trimethyl-4-oxoadamantan-1-yl trifluoromethanesulfonate, 4m. 1H NMR (500 MHz, CDCl3) δ 1.79 (m, 2H), 1.70 (bs, 2H), 1.77 (bd, J = 13.0 Hz, 2H), 1.52 (bd, J = 15.0 Hz, 2H), 1.47 (m, 2H), 0.99 (s, 3H), 0.96 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 217.1, 69.3, 52.2, 51.5, 49.6, 46.3, 33.9, 27.9, 21.8. GCMS (EI+) found 340.1, calculated for C14H19F3O4S 340.0.

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7,7'-Oxybis(1,3,5-trimethyladamantan-2-one), 4n. 1H NMR (500 MHz, CDCl3) δ 1.89 (d, J = 11.5 Hz, 4H), 1.78 (m, 4H), 1.56 (s, 4H), 1.48 (m, 8H), 0.97 (s, 6H), 0.96 (s, 12H).

13

C NMR (125 MHz,

CDCl3) δ 217.5, 75.2, 52.3, 52.2, 50.1, 46.6, 33.9, 28.5, 22.4. GCMS (EI+) found 398.4, calculated for C26H38O3 398.3.

N-(3,5,7-Trimethyl-4-oxoadamantan-1-yl)acetamide, 4o. 1H NMR (500 MHz, CDCl3) δ 5.41 (bs, 1H), 1.97 (s, 4H), 1.94 (s, 2H), 1.90 (s, 3H), 1.51 (s, 4H), 0.94 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 217.2, 169.8, 52.9, 52.3, 48.5, 45.9, 45.8, 32.7, 28.2, 24.5, 22.2. HRMS (ESI, m/z): 250.1799, calculated for C15H23NO2H (M+H)+ 250.1807.

5-Ethynyl-1,3,7-trimethyladamantan-2-one, 4p. 1H NMR (500 MHz, CDCl3) δ 2.13 (s, 1H), 1.91 (bd, J = 12.5 Hz, 2H), 1.83-1.80 (m, 4H), 1.52-1.47 (m, 4H), 0.95 (s, 6H), 0.94 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 217.1, 89.4, 68.0, 52.2, 50.5, 47.5, 45.5, 31.5, 31.3, 28.5, 22.3. HRMS (ESI, m/z): 217.1581, calculated for C15H21OH (M+H)+ 217.1592.

5-(Bromomethyl)-7-hydroxy-1,3-dimethyladamantan-2-one, 4q. 1H NMR (500 MHz, CDCl3) δ 3.27 (s, 2H), 2.60 (s, 1H), 1.79 (m, 4H), 1.69 (m, 2H), 1.59 (s, 4H), 0.99 (s, 6H).

13

C NMR (125 MHz,

CDCl3) δ 216.1, 68.8, 51.7, 48.3, 46.1, 45.9, 43.5, 37.7, 22.0. HRMS (ESI, m/z): 287.0628, calculated for C13H19BrO2H (M+H)+ 287.0647.

5-(Bromomethyl)-7-methoxy-1,3-dimethyladamantan-2-one, 4r. 1H NMR (500 MHz, CDCl3) δ 3.27 (s, 2H), 3.25 (s, 3H), 1.78 – 1.70 (m, 6H), 1.62 – 1.56 (m, 4H), 1.00 (s, 6H).

13

C NMR (125 MHz,

CDCl3) δ 216.2, 72.5, 49.1, 48.5, 47.7, 45.7, 43.7, 41.9, 37.3, 22.2. HRMS (ESI, m/z): 301.0785, calculated for C14H21BrO2H (M+H)+ 301.0803.

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5-Bromo-7-(bromomethyl)-1,3-dimethyladamantan-2-one, 4s. 1H NMR (500 MHz, CDCl3) δ 3.23 (s, 2H), 2.33 (m, 2H), 2.21 (m, 2H), 1.67 (s, 4H), 0.99 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 214.2, 59.1, 55.5, 49.5, 48.0, 47.6, 42.9, 38.7, 21.8. HRMS (ESI, m/z): 348.9797, calculated for C13H18Br2OH (M+H)+ 348.9803.

5-Iodo-7-(iodomethyl)-1,3-dimethyladamantan-2-one, 4t. 1H NMR (500 MHz, CDCl3) δ 3.06 (s, 2H), 2.52 (s, 2H), 2.51 (d, J = 11.0 Hz, 2H), 2.41 (d, J = 12.5 Hz, 2H), 1.75 (d, J = 12.0 Hz, 2H), 1.68 (d, J = 11.5 Hz, 2H), 0.98 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 214.2, 58.8, 53.7, 49.0, 48.6, 39.9, 37.5, 21.6, 19.1. HRMS (ESI, m/z): 444.9519, calculated for C13H18I2OH (M+H)+ 444.9525.

7-Methoxy-3,5-dimethyl-4-oxoadamantan-1-yl)methyl)mercury(II) chloride, 4u. 1H NMR (400 MHz, CDCl3) δ 3.16 (s, 3H), 2.05 (s, 2H), 1.67 (m, 4H), 1.55 (m, 4H), 1.44 (m, 4H), 0.89 (s, 6H).

1,3-Diethyl-5-methyl-7-phenyladamantan-2-one, 7a. 1H NMR (500 MHz, CDCl3) δ 7.39 (bd, J = 8.4 Hz, 2H), 7.34 (bt, J = 7.6 Hz, 2H), 7.22 (bt, J = 6.8 Hz, 1H), 1.94 (bd, J = 12 Hz, 2H), 1.87 (s, 2H), 1.84 (bd, J = 12.4 Hz, 2H), 1.56 (m, 4H), 1.47 (qd, J = 7.2, 2.4 Hz, 4H), 1.04 (s, 3H), 0.85 (t, J = 7.6 Hz, 6H).

13

C NMR (125 MHz, CDCl3) δ 218.0, 147.9, 128.2, 126.1, 124.8, 49.3, 48.6, 48.55, 48.50, 37.9,

31.6, 29.1, 28.3, 7.8. HRMS (ESI, m/z): 297.2209, calculated for C21H28OH (M+H)+ 297.2218.

5-Methyl-7-phenyl-1,3-dipropyladamantan-2-one, 7b.

1

H NMR (500 MHz, CDCl3) δ 7.38 (bd, J =

8.0 Hz, 2H), 7.34 (bt, J = 7.5 Hz, 2H), 7.23 (bt, J = 7.0 Hz, 1H), 1.95 (bd, J = 12.5 Hz, 2H), 1.86 (s, 2H), 1.85 (d, J = 12 Hz, 2H), 1.60 (d, J = 12.5 Hz, 2H), 1.55 (d, J = 12.5 Hz, 2H), 1.38 (m, 4H), 1.28 (m, 4H), 1.02 (s, 3H), 0.92 (t, J = 7.0 Hz, 6H).

13

16

C NMR (125 MHz, CDCl3) δ 218.1, 148.0, 128.4,


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126.2, 124.9, 50.0, 49.1, 48.8, 48.6, 38.4, 38.0, 31.8, 29.3, 16.7, 15.0. HRMS (ESI, m/z): 325.2522, calculated for C23H32OH (M+H)+ 325.2531.

5-Methyl-1,3,7-triphenyladamantan-2-one, 7c.

1

H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 7.0 Hz,

2H), 7.42-7.20 (m, 13H), 2.81 (d, J = 12.0 Hz, 2H), 2.45 (d, J = 12.5 Hz, 2H), 2.38 (d, J = 12.5 Hz, 2H), 2.09 (d, J = 12.5 Hz, 2H), 2.05 (s, 2H), 1.28 (s, 6H), 1.24 (s, 3H).

13

C NMR (125 MHz, CDCl3) δ 212.7,

147.4, 142.8, 128.9, 128.8, 128.6, 128.1, 127.1, 126.6, 54.0, 50.7, 49.8, 48.2, 38.6, 32.4, 29.7. HRMS (ESI, m/z): 393.2204, calculated for C29H28OH (M+H)+ 393.2218.

5-Amino-1,3,7-trimethyladamantan-2-one, 8. 1H NMR (500 MHz, CDCl3) δ 1.65 (d, J = 11.5 Hz, 2H), 1.53 (m, 4H), 1.43 (d, J = 11.5 Hz, 2H), 1.24 (s, 2H), 0.96 (s, 3H), 0.94 (s, 6H).

13

C NMR (125

MHz, CDCl3) δ 218.0, 53.3, 52.4, 50.8, 46.0, 33.1, 28.2, 22.2. HRMS (ESI, m/z): 208.1691, calculated for C13H21NOH (M+H)+ 208.1701.

Acknowledgements. This material is based upon work supported by the National Science Foundation under equipment grant no. CHE-1048804.

Supporting Information Available: NMR spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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References and Notes

(1) Landa, S.; Machacek, V. Collect. Czech. Chem. Commun. 1933, 5, 1. (2) (a) Schleyer, P. v. R. J. Am. Chem. Soc. 1957, 79, 3292. (b) Schleyer, P. v. R.; Donaldson, M. M.; Nicholas, R. D.; Cupas, C. Org. Synth. 1973, Coll. Vol. 5, 16. (3) For selected publications on adamantanes in medicinal chemistry, see: (a) Wanka, L.; Iqbal, K., Schreiner, P. R. Chem. Rev. 2013, 113, 3516. (b) Lamoureux, G.; Artavia, G. Curr. Med. Chem. 2010, 17, 2967. (c) Schwab, R. S.; England, A. C., Jr.; Poskanzer, D. C.; Young, R. R. J. Am. Med. Assoc. 1969, 208, 1168. (d) Rapala, R. T.; Kraay, R. J.; Gerzon, K. J. Med. Chem. 1965, 8, 580. (e) Gerzon, K.; Kau, D. J. Med. Chem. 1967, 10, 189. (4) (a) Gerzon, K.; Krumalns, E. V.; Brindle, R. L.; Marshall, F. J.; Root, M. A. J. Med. Chem. 1963, 6, 760. (b) Scherm, M.; Peter, D.; Jamiak, B. Ger. Offen. DE2219256, Nov. 8, 1973. (5) Moosophon, P.; Kanokmedhakul, S.; Kanokmedhakul, K.; Soytong, K. J. Nat. Prod. 2009, 72, 1442. (6) Jung, M. E.; Lee, G. S.; Pham, H. V.; Houk, K. N. Org. Lett. 2014, 16, 2382. (7) (a) Aigami, K.; Inamoto, Y.; Takaishi, N.; Hattori, K. Takatsuki, A.; Tamura, G. J. Med. Chem. 1975, 18, 713. (b) Olah, G. A.; Farooq, O.; Farnia, M. F.; Wu, A. J. Org. Chem. 1990, 55, 1516. (c) Olah, G. A.; Prakash, G. K. S.; Shih, J. G.; Krishnamurthy, V. V.; Mateescu, G. D.; Liang, G.; Sipos, G.; Buss, V.; Gund, T. M.; Scheleyer, P. v. R. J. Am. Chem. Soc. 1985, 107, 2764. (d) Olah, G. A.; Lee, C. S.; Prakash, G. K. S.; Moriarty, R. M.; Rao, M. S. C. J. Am. Chem. Soc. 1993, 115, 10728. (e) Olah, G. A.; Török, B.; Shamma, T.; Török, M.; Prakash, G. K. S. Catal. Lett. 1996, 42, 5. (f) Prakash, G. K. S.; Yan, P.; Török, B.; Bucsi, I.; Tanaka, M.; Olah, G. A. Catal. Lett. 2003, 85, 1. (g) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. Synthesis 1990, 646. (8) Stetter, H.; Gärtner, J. Chem. Ber. 1966, 99, 925. (9) (a) Kozlikovskii, Ya. B.; Koschii, V. A.; Rodionov, V. N.; Yurchenko, A. G.; Mudryi, A. P. Russ. J. Org. Chem. 1988, 24, 2337. (b) Kozlikovskii, Ya. B.; Koschii, V. A.; Rodionov, V. N.; Yurchenko, A. G.; Mudryi, A. P. Russ. J. Org. Chem. 1989, 25, 294. (c) Gubernatorov, V. K.; Kogai, B. E.; Sokolenko, V. A. Izv. Akad. Nauk, Ser. Khim. 1983, 1203. (10) The 2-substituted isomer has one absorption at low field, δ 6.48, and two absorptions at higher field, δ 6.01 and 5.94, while the pattern for the 3-substituted isomer was the opposite, namely two 18


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absorptions at low field, δ 6.53 and 6.40, and one absorption at higher field, δ 6.04. For similar examples, see: von der Saal, W.; Reinhardt, R.; Stawitz, J.; Quast, H. Eur. J. Org. Chem. 1998, 1645. (11) Iovel, I.; Fleisher, M.; Popelis, Yu.; Shimanska, M.; Lukevits, E. Chem. Heterocycl. Compd. 1995, 31, 140. (12) (a) Sánchez-Mendoza, E.; Hernández-Trujillo, J. Magn. Reson. Chem. 2010, 48, 866. (b) Lukevics, E. Ya.; Ignatovich, L. M.; Goldberg, Yu. S.; Shymanskaya, M. U. Khim. Geterotsikl. Soedin. 1986, 853. (13) (a) Ref. 8. (b) Sohar, P.; Kuszmann, J.; Neder, A. Tetrahedron 1986, 42, 2523. (c) Stetter, H.; Lennartz, J. Liebigs Ann. Chem. 1977, 1807. (14) Olah, G. A.; Gupta, B. G. B.; J. Org. Chem. 1980, 45, 3532. (15) (a) Serguchev, Y. A.; Ponomarenko, M. V.; Lourie, L. F.; Chernega, A. N. J. Fluorine Chem. 2003, 123, 207. (b) Kogai, B. E.; Gubernatorov, V. K.; Sokolenko, V. A. Zh. Org. Khim. 1984, 20, 2554. (16) (a) Ref. 8. (b) Chizhov, O. S.; Novikov, S. S.; Karpenko, N. F.; Yurchenko, A. G. Izv. Akad. Nauk, Ser. Khim. 1972, 1510. (c) Stepanov, F. N.; Baklan, V. F.; Isaev, S. D. Zh. Org. Khim. 1965, 1, 280. (17) (a) Schleyer, P. v. R.; Fort, R. C.; Watts, W. E.; Comisarow, M. B.; Olah, G. A. J. Am. Chem. Soc. 1964, 86, 4195. (b) Ref. 7c.

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TOC Graphic

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Synthesis of Highly Substituted Adamantanones from Bicyclo[3.3.1

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